This invention relates to the use of improved regimens for the administration of finafloxacin for the treatment of uncomplicated and complicated urinary tract infections (UTIs) and pyelonephritis.
Finafloxacin is a novel fluoroquinolone and combines essential features required to successfully treat bacterial infections: good activity against Gram positive, Gram negative and anaerobic pathogens. Finafloxacin (INN International Nonproprietary Name) is an antibiotic of the class of the quinolone carboxylic acids of the following formula: (−)-8-cyano-1-cyclopropyl-6-fluoro-7-[(4aS,7aS)-hexahydropyrrolo[3,4-B]-1,4-oxazin-6(2H)-yl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid. Finafloxacin has been described as useful in the treatment of H. pylori infections (EP0946176) or of ophthalmic, otic, or nasal infections (U.S. Pat. No. 8,536,167). Finafloxacin and derivatives thereof can be synthesized according to the methods described in WO 98/26779 by Matzke et al., the contents of which are herein incorporated by reference in their entirety.
In vitro and in vivo microbiological assessments show that finafloxacin is effective in animal infection models. The high activity of finafloxacin at the site of infection is thereby attributed, in part, to its unique enhanced antibacterial activity at pH values below neutral.
The increased activity of finafloxacin in an acidic environment was found to be exactly opposite to that of all marketed quinolones, which substantially reduced activity under these conditions. Therefore finafloxacin appears to be an excellent medication in all indications associated with a low pH environment. The spectrum of antibacterial activity of finafloxacin covers the vast majority of pathogens predominant in UTIs, intra-abdominal infections, skin infections and other indications.
The European Association of Urology advises specific regimens for the treatment of the various forms of UTIs. For mild and moderate cases of acute uncomplicated UTI the guidelines of the European Association of Urology (2014) recommends an oral therapy with various antibiotics for 3-7 days, amongst them regimens with fluoroquinolones for 3 days. For mild and moderate cases of acute uncomplicated pyelonephritis an oral therapy of 5-14 days with different antibiotics is recommended, amongst them regimens with fluoroquinolones for 7-10 days. For complicated UTIs the guidelines advise the treatment for 7-21 days with an initial parenteral therapy for hospitalized patients which can subsequently be switched to an oral treatment.
Pathogens exposed to the nosocomial environment develop resistances through mutation due to selective pressure by antibiotic or antiseptic medications used and leading experts to state that nosocomial UTIs comprise perhaps the largest institutional reservoir of nosocomial antibiotic resistant pathogens. UTIs are among the most prevalent infectious diseases in ambulatory and hospitalized populations, with a substantial financial burden on the society. Up to 40% of women will develop a UTI at least once in their lifetime, and a significant number of them will have recurrences. In the USA the treatment of UTI accounts for about 15% of all community-prescribed antibiotics and every year UTIs result in more than 100,000 hospital admissions. UTIs are also considered to be responsible for at least 40% of all nosocomial infections, most of which are being catheter associated.
It is therefore medicinally desirable to avoid a hospital treatment or at least to reduce the length of the hospital stay of patients suffering from UTIs, and accordingly a need for drugs giving the physicians that possibility.
Thus, there is the need for treatment regimens with reduced treatment durations in order to minimize the likelihood of developing resistances due to selective pressure by antibiotic medications. In case of necessary hospitalizations shorter stays in hospital should reduce the risk of nosocomial infections and of generating drug-resistant strains through extended therapy. Ideally, a parenteral therapy for hospitalized patients should be avoided. Therefore, in case of uncomplicated UTI shorter treatment periods than the recommended 3-7 days would be beneficial. In case of complicated UTI and pyelonephritis reduced treatment durations of less than 7 days would have clear advantages. Especially treatment regimens without the necessity of parenteral therapy are preferable because any hospitalization with the risk of nosocomial infections could be avoided.